Serotonin (5-hydroxytryptamine) (5-HT) receptors play a critical role in many physiological and behavioral functions in humans and animals. These functions are mediated through various 5-HT receptors distributed throughout the body. There are now approximately fifteen different human 5-HT receptor subtypes that have been cloned, many with well-defined roles in humans. A recently identified 5-HT receptor subtype is the 5-HT6 receptor, first cloned from rat tissue in 1993 (Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W. Molecular Pharmacology 1993, 43, 320-327) and subsequently from human tissue (Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Sibley, D. R. Journal of Neurochemistry 1996, 66, 47-56). The receptor is a G-protein coupled receptor (GPCR) positively coupled to adenylate cyclase (Ruat, M., Traiffort, E., Arrang, J-M., Tardivel-Lacombe, L., Diaz, L., Leurs, R., and Schwartz, J.-C., Biochemical Biophysical Research Communications 1993, 193, 268-276). The receptor is found almost exclusively in the central nervous system (CNS) areas both in rat and in human. In situ hybridization studies of the
5-HT6 receptor in rat brain using mRNA indicate principal localization in the areas of 5-HT projection including striatum, nucleus accumbens, olfactory tubercle, and hippocampal formation (Ward, R. P.; Hamblin, M. W.; Lachowicz, J. E.; Hoffman, B. J.; Sibley, D. R.; Dorsa, D. M. Neuroscience 1995, 64, 1105-1111).
5-HT6 receptor in rat brain using mRNA indicate principal localization in the areas of 5-HT projection including striatum, nucleus accumbens, olfactory tubercle, and hippocampal formation (Ward, R. P.; Hamblin, M. W.; Lachowicz, J. E.; Hoffman, B. J.; Sibley, D. R.; Dorsa, D. M. Neuroscience 1995, 64, 1105-1111).
There are many potential therapeutic uses for 5-HT6 ligands in humans based on direct effects and on indications from available scientific studies. These studies include the localization of the receptor, the affinity of ligands with known in vivo activity, and various animal studies conducted so far.
One potential therapeutic use of modulators of 5-HT6 receptor function is in the enhancement of cognition and memory in human diseases such as Alzheimer's. The high levels of receptor found in important structures in the forebrain, including the caudate/putamen, hippocampus, nucleus accumbens, and cortex suggest a role for the receptor in memory and cognition since these areas are known to play a vital role in memory (Gerard, C.; Martres, M.-P.; Lefevre, K.; Miguel, M. C.; Verge, D.; Lanfumey, R.; Doucet, E.; Hamon, M.; E I Mestikawy, S. Brain Research, 1997, 746, 207-219). The ability of known 5-HT6 receptor ligands to enhance cholinergic transmission also supported the potential cognition use (Bentley, J. C.; Boursson, A.; Boess, F. G.; Kone, F. C.; Marsden, C. A.; Petit, N.; Sleight, A. J. British Journal of Pharmacology, 1999, 126(7), 1537-1542). Studies have found that a known 5-HT6 selective antagonist significantly increased glutamate and aspartate levels in the frontal cortex without elevating levels of noradrenaline, dopamine, or 5-HT. This selective elevation of neurochemicals known to be involved in memory and cognition point to a role for 5-HT6 ligands in cognition (Dawson, L. A.; Nguyen, H. Q.; Li, P. British Journal of Pharmacology, 2000, 130(1), 23-26). Animal studies of memory and learning with a known selective 5-HT6 antagonist found positive effects (Rogers, D. C.; Hatcher, P. D.; Hagan, J. J. Society of Neuroscience, Abstracts 2000, 26, 680).
A related potential therapeutic use for 5-HT6 ligands, particularly antagonists, is the treatment of attention deficit disorders (ADD) and Attention Deficit Hyperactivity Disorder (ADHD) in both children and adults. Ernst, M; Zametkin, A. J.; Matochik, J. H.; Jons, P. A.; Cohen, R. M. Journal of Neuroscience 1998, 18(15), 5901-5907).
5-HT6 ligands also show potential for the treatment of schizophrenia and depression. For example, clozapine (an effective clinical antipsychotic) has high affinity for the 5-HT6 receptor subtype. Also, several clinical antidepressants have high affinity for the receptor as well and act as antagonists at this site (Branchek, T. A.; Blackburn, T. P. Annual Reviews in Pharmacology and Toxicology 2000, 40, 319-334).
Impaired cognitive function is a core feature of schizophrenia, exhibiting numerous manifestations, including a fundamental defect in the patient's ability to manipulate available information. Weinberger et. al. International clinical psychopharmacology, 1997, 12, 38-40. The magnitude of the cognitive deficit in schizophrenia is considerable and remains relatively stable despite fluctuations in other symptoms. Id. The degree of dysfunction also has a high predictive value for long-term disability. Id. Good cognitive function depends upon the brain's ability to prioritize tasks and to switch from parallel processing to sequential processing when the processing load is excessive. Id. This requires working executive memory. Neuroimaging and functional analyses suggest that such cognitive function relies upon unimpaired prefrontal activity. Id. There is increasing evidence that antipsychotic drugs with 5-hydroxytryptamine-blocking activity (particularly 5-HT2a) produce better cognitive function in patients with schizophrenia than drugs with predominantly dopamine (D)2-blocking activity (conventional neuroleptics). Id. Accordingly, improving or stabilizing cognitive function in patients suffering from schizophrenia through administration of antipsychotic drugs with 5-hydroxytryptamine-blocking activity will ideally lead to improved patient outcomes.
The neurocognitive deficits in schizophrenia are considered a separate area of the illness that is relatively independent of psychotic symptoms and closely related to functional outcome. These neurocognitive deficits include working memory, attention/vigilance, verbal learning and memory, visual learning and memory, reasoning and problem-solving, speed of processing, and social recognition (Green M F, Nuechterlein K H, Gold J M, et al. “Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria”, Biol. Psychiatry 2004; 56:301-307).
Further, recent in vivo studies in rats indicate 5-HT6 modulators may be useful in the treatment of movement disorders including epilepsy (Stean, T.; Routledge, C.; Upton, N. British Journal of Pharmacology 1999, 127 Proc. Supplement 131P and Routledge, C.; Bromidge, S. M.; Moss, S. F.; Price, G. W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.; Stean, T.; Upton, N.; Clarke, S. E.; Brown, A. M. British Journal of Pharmacology 2000, 130(7), 1606-1612).
Taken together, the above studies strongly suggest that compounds which are 5-HT6 receptor modulators, i.e. ligands, may be useful for therapeutic indications including: the treatment of symptoms associated with Alzheimer's disease, such as dementia, a deficit in memory, cognition, and learning; the treatment of personality disorders such as schizophrenia; the treatment of behavioral disorders, e.g., anxiety, depression and obsessive compulsive disorders; the treatment of ADD and ADHD; the treatment of motion or motor disorders such as Parkinson's disease and epilepsy; the treatment of diseases associated with neurodegeneration such as stroke and head trauma; or withdrawal from drug addiction including addiction to nicotine, alcohol, among others.
Because 5-HT6 receptors are located almost exclusively in the brain, modulation of the receptors by parenterally administered drugs requires that the drugs cross the blood brain barrier. The blood brain barrier is composed of brain capillary endothelial cells with continuous tight junctions making it virtually impossible for compounds to enter into the brain around the cells. J. Bryan, Pharmaceutical Journal, 273 (2004) 475-476. Instead, access to the brain is limited to passive diffusion or active transport through the endothelial cells. G&G, Pharmaceutical Basis of Therapeutics, 10th Ed at page 10. Accordingly, bioavailable parenterally administered compounds affecting 5-HT6 activity must not only possess favorable solubility profiles in order to successfully enter the blood stream, but they also need to cross the blood brain barrier in order to target the 5-HT6 receptors. Advantageously, this invention provides compounds which are capable of modulating 5-HT6 receptor activity and are bioavailable.
Recent clinical and preclinical efforts on 5-HT6 ligands have been reviewed by Rudy Schreiber, Andrew Sleight and Marie Woolley, “5-HT6 Receptors as Targets for the Treatment of Cognitive Deficits in Schizophrenia” in The Receptors Book The Serotonin Receptors, Humana Press, 2006, Pages 495-515, Edited by Bryan L. Roth; Johnson C N, Ahmed M, Miller N D, “5-HT6 receptor antagonists: prospects for the treatment of cognitive disorders including dementia” Curr. Opin. Drug Discov. Devel. 11 (5): 642-54 (September 2008), Jorg Holenz, Petrus J. Pauwels, Jose Luis Diaz, Ramon Merce, Xavier Codony, and Helmut Buschmann, “Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents”, Drug Discovery Today, 11 (7/8) April 2006, and Robin Emsley, “Drugs in development for the treatment of schizophrenia”, Expert Opinion on Investigational Drugs, 18 (8) 1103-1118, August 2009.
Nine 5-HT6 ligands have entered human clinical trials. Lu-AE-58054 from Lundbeck is in schizophrenia cognitive disorder Phase II trials, SAM-531 from Wyeth is in Alzheimer's disease Phase II trials, SYN-114 from Synosia Therapeutics is in Alzheimer's disease Phase I trials, PRX-07034 from EPIX Pharmaceuticals Inc, is in schizophrenia, Alzheimer's disease, and obesity Phase Ib trials, SUVN-502 from Suven Life Sciences Ltd. is in Alzheimer's disease Phase I trials, SB-742457 from GlaxoSmithKline is in cognitive dysfunction associated with Alzheimer's disease Phase II trials, LY-483518 from Lilly, which is licensed to Saegis Pharmaceuticals (SGS-518) is in cognitive impairment associated with schizophrenia Phase IIa trials, SAX-187 from Wyeth is currently in anxiety Phase I trials, and SB-271046 from GlaxoSmithKline was in Alzheimer's disease and schizophrenia Phase I trials but has been discontinued (probably because of low penetration of the blood-brain barrier).
The structures of 1-[(3-fluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-benzimidazole, 1-[(2-fluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-benzimidazole, 1-[(3-chlorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-benzimidazole, 1-(1-naphthalenylsulfonyl)-4-(1-piperazinyl)-1H-benzimidazole, and 1-[(2,5-dichlorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-benzimidazole were generated by ChemZoo, Inc. of Winston-Salem, N.C. in 2008 through the ChemSpider data base. However, the compounds do not appear to ever have been offered for sale. No information is provided as to their ability to bind to the 5-HT6 receptor or to any pharmacological effect or use of these compounds. There is no evidence they were ever made and no method for making the compounds is provided.
The invention provides compounds useful as therapeutic agents in the treatment of a variety of conditions related to or affected by 5-HT6 receptor activity, including psychoses (e.g., schizophrenia, anxiety, or depression), motor disorders (e.g., Parkinson's disease), anxiety, depression, drug addiction, obsessive compulsive disorder, attention deficit disorder, or any condition which is known to be related to or affected by the 5-HT6 receptor. These and other features of this invention will become more apparent by the detailed description set forth herein below.